On sustained-release microcapsules of various physiologically active polypeptides or low molecular water-soluble drugs, many reports have been made [Critical Reviews in Therapeutic Drug Carrier Systems, 12, 1-9 (1995); JP-A H2(1990)2-503315; EP-A-0586238; J. Pharm. Sci., 75, 750-755 (1986); JP-A S57(1987)-118512]. Most of the microcapsules so far reported have the following drawbacks:
(1) in the manufacturing process, the amount of the water-soluble drug leaked to the outer aqueous phase is relatively large to invite a relatively low entrapment ratio of the drug, (2) the resulting microcapsules are generally porous and cause a relatively large initial release, and (3) in the manufacturing process, the physiologically active substance is denatured to invite insufficient bioavailability. Thus, at the present stage, sustained release of the drug over a desirable long period have not yet been succeeded.
In JP-A S61(1986)-63613, improvement of sustained release of microspheres was reported. That is, there is described that for the purpose of preventing decrease of release rate of the active ingredient a certain hour after administration of microspheres whose base is polylactic acid, in an organic solvent of polylactic acid to which the active ingredient is dispersed, an oil soluble additive (medium chain fatty acid triglyceride, a lower fatty acid triglyceride, etc.) which is soluble in said solvent and which is biodegradable is uniformly dissolved. However, there is no suggestion on application to the other bases nor on preparation of microcapsules using a solution of the active ingredient.
In JP-A H8(1996)-151321 [EP-A-0709085], there is disclosed microcapsules which contains an amorphous type water-soluble physiologically active substance and polymer, and which are produced from a S/O/W type emulsion. However, there is no description on a process for producing microcapsules using a solution of a drug as an inner aqueous phase nor on a method using metal complex of a water-soluble physiologically active peptide.
In EP 0765660, there is disclosed microcapsules which contains an amorphous type 2-piperazinone-1-acetic acid derivative, and in a production method thereof, a S/O/W type emulsion is employed. However, there is no description on a process for producing microcapsules using a solution of a drug as an inner aqueous phase nor on a method using metal complex of a water-soluble physiologically active peptide.
In general, in a process for producing microcapsules of a water-soluble physiologically active substance, it is more advantageous to employ a W/O type emulsion than a S/O type emulsion where the drug is used as solid substances in view of equivalency of drug content or operation, and it is desired to employ a W/O type emulsion in an industrial manufacture with large scale.